Fasciola hepatica extracellular vesicles - the key to parasite control?

肝片形吸虫病是一种常见的、经济上重要的家畜疾病。它是由一种名为肝片形吸虫（Fasciola hepatica）的寄生扁形虫（也称为肝吸虫）引起的，这种寄生扁形虫感染了全世界3亿多头牛和2.5亿只羊，导致全球农业因生产力下降而损失30多亿美元。它在英国也很普遍，由于动物状况不佳以及牛奶和肉类产量显著减少，每年仅养牛业就损失约2300万英镑。虽然传统上被认为是一种牲畜疾病，但片形吸虫病是一种新兴的人类疾病，估计全世界有240万人感染。治疗肝吸虫感染的首选药物是三氯苯达唑。然而，就像在我们的医院肆虐的耐药细菌一样，耐三氯苯达唑的吸虫现在正在英国/爱尔兰、欧洲大陆和澳大利亚迅速蔓延。这使得农民几乎没有什么可以对抗这种疾病，因为大多数剩余的药物对未成熟的吸虫无效，这些吸虫对受感染的动物造成最大的伤害。随着肝吸虫感染的空前爆发，预计在未来60年内将在英国发生，新的策略的发展，为F。控制肝病是当务之急。抗药性的蔓延，加上消费者对食品中存在化学残留物的担忧加剧，推动了对抗片形吸虫疫苗的研究。尽管有一些早期的成功，但仍然没有商业上可用的抗F。肝。这很可能是由于寄生虫影响宿主免疫反应的惊人能力。片形吸虫是一种成熟的免疫调节剂，引导宿主免疫反应远离对它们最有害的类型-Th1反应-并调节反应以创造一个优化成功喂养和繁殖的环境-Th2反应。我们已经发现寄生虫释放的特定分子负责这种免疫调节，我们相信靶向释放这些分子可能是寄生虫控制的关键。最近的研究表明，分子可以通过包装到称为细胞外囊泡（EV）的囊中从一个细胞转移到另一个细胞。我们的合作者Antonio Marcilla博士（瓦伦西亚大学）最近发现，电动汽车也从F。我们现在知道它们含有许多已知的免疫调节剂。因此，我们提出，阻止寄生虫释放EV将阻止包装在内部的免疫调节分子转移到宿主免疫细胞。这将允许Th1免疫应答占上风，导致寄生虫的排出。为了实现这一目标，我们将使用一种称为RNA干扰（RNAi）的新技术来“关闭”参与包装和释放寄生虫EV的特定分子。然后，我们将能够确定这种方法是否可以提高宿主的免疫反应并消除寄生虫。这是一个多学科的项目，将建立在片形吸虫生物学和技术进步的最新发现。因此，我们已经组建了一个强大的国家和国际合作者网络，他们将在RNAi（Maule教授），免疫学（道尔顿教授和Donnelly博士）和EV生物学（Marcilla博士）方面提供大量支持和专业知识。我们设想，这项研究将产生特定的目标，用于控制肝吸虫感染（通过新药或疫苗），这将是商业上有吸引力的，并可转移到人类和动物的其他寄生虫感染。

Fasciolosis is a common, and economically important, disease of livestock. It is caused by a parasitic flatworm called Fasciola hepatica (also known as the liver fluke) that infects more than 300 million cattle and 250 million sheep worldwide resulting in losses of over $3 billion to global agriculture through lost productivity. It is also widespread in the UK, and costs the cattle farming industry alone around £23 million each year as a result of poor animal condition and a significant reduction of milk and meat yields. Although traditionally regarded as a disease of livestock, fasciolosis is an emerging disease of humans with an estimated 2.4 million people infected worldwide. The drug of choice against liver fluke infection is triclabendazole. However, just like the drug-resistant bacteria that are wreaking havoc in our hospitals, triclabendazole-resistant fluke are now rapidly spreading throughout the UK/Ireland, continental Europe and Australia. This has left farmers with little to combat the disease as most remaining drugs are ineffective against the immature flukes that cause most damage to the infected animal. With unprecedented outbreaks of liver fluke infection predicted to occur in the UK over the next 60 years, the development of new strategies for F. hepatica control is most urgent. The spread of drug resistance, together with heightened consumer concerns about the presence of chemical residues in food, has fuelled the search for anti-Fasciola vaccines. Despite some early successes there are still no commercially-available vaccines against F. hepatica. This is most likely due to the striking ability of the parasite to influence the host immune response. Fasciola is an accomplished immune-modulator, directing the host immune response away from the type that is most damaging to them - a Th1 response - and regulating the response to create an environment that optimises successful feeding and reproduction - a Th2 response. We have found that specific molecules released by the parasites are responsible for this immune-modulation and we believe that targeting the release of these may be the key to parasite control. Recent research has shown that molecules can be transferred from one cell to another by being packaged into sacs called extracellular vesicles (EVs). Our collaborator Dr Antonio Marcilla (University of Valencia) recently found that EVs are also released from F. hepatica and we now know that they contain many known immunomodulators. Thus, we propose that preventing the release of EVs from the parasite will stop the transfer of the immunomodulatory molecules packaged inside to host immune cells. This will allow a Th1 immune response to prevail leading to expulsion of the parasite. To achieve this we will use a new technique called RNA interference (RNAi) to "switch off" particular molecules that are involved in packaging and release of EVs from the parasite. We will then be able to determine if this approach can give the host`s immune response a boost and eliminate the parasite. This is a multidisciplinary project which will build on recent discoveries in Fasciola biology and advances in technology. As such, we have assembled a strong network of national and international collaborators who will provide considerable support and expertise in RNAi (Prof Maule), immunology (Prof Dalton and Dr Donnelly) and EV biology (Dr Marcilla). We envisage that specific targets will emerge from this research for control of liver fluke infections (by new drugs or vaccines) that will be commercially attractive and transferable to other parasitic infections of humans and animals.